Advanced metastatic melanoma is one of the deadliest forms of skin cancer, characterized by a strong metastatic propensity and plasticity in developing resistance to therapies. Despite the improvement of clinical responses resulting from BRAFi, the rapid development of adaptive resistance to the drug in most tumors or the intrinsic resistance to the drug in subset of tumors remains a major obstacle and impedes the long-term clinical benefits of BRAF-targeted therapies. We identified the E3 ligase RNF125 as an important regulator that confers both intrinsic and adaptive BRAFi-resistance. RNF125 was found to regulate the stability of JAK1, which in turn controls the expression of EGFR. RNF125 expression is attenuated in BRAFi-resistant melanomas, resulting in increased JAK1 and concomitantly, EGFR expression. Notably, RNF125 also regulates two key components of the immune checkpoint ligand, PD-L1 and PD-L2, suggesting it plays equally important role in defining immune checkpoint control. These observations provide the basis for our hypothesis that RNF125 represents a key regulatory component in resistance to BRAFi and response to immune checkpoint-based therapies. To test our hypothesis, we will (i) define mechanisms underlying the regulation of RNF125 expression in melanoma cell by cell intrinsic or extrinsic cues, (ii) define the components and pathways by which RNF125 controls immune checkpoint functions, (iii) evaluate the role of RNF125-JAK1 regulatory axis in melanoma response to therapies in immunocompetent congenic murine model. Our proposed studies will define the role of RNF125 in melanoma resistance to BRAFi as well as in the regulation of immune checkpoint, which are expected to propel the development of novel therapeutic modalities to BRAFi-resistant tumors.